tbuckley/cabot-search huggingface dataset:
Serological responses to three doses of SARS-CoV-2 vaccination in inflammatory bowel disease
Authors: Joshua Quan, Christopher Ma, Remo Panaccione, Lindsay Hracs, Nastaran Sharifi, Michelle Herauf, Ante Makovinović, Stephanie Coward, Joseph W Windsor, Léa Caplan, Richard J M Ingram, Jamil N Kanji, Graham Tipples, Jessalyn K Holodinsky, Charles N Bernstein, Douglas J Mahoney, Sasha Bernatsky, Eric I Benchimol, Gilaad G Kaplan
Journal: Gut (2022)
The road to biologics in patients with hidradenitis suppurativa: a nationwide drug utilization study
Authors: Hans Christian Ring, Yiqiu Yao, Julia-Tatjana Maul, John R. Ingram, John W. Frew, Jonathan Thorsen, Mia-Louise Nielsen, Jashin J. Wu, Jacob P. Thyssen, Simon F. Thomsen, Alexander Egeberg
Journal: British Journal of Dermatology (2022)

Prolonged systemic antibiotic treatment is often a part of management of hidradenitis suppurativa (HS). Although biologic therapies are now available, the patient's treatment journey leading to biologic therapy is unclear.To examine treatment patterns and duration of systemic treatment use in patients with HS preceding biologic therapy.We identified all patients with HS receiving treatment with biologics in the Danish National Patient Registry from 2010 to 2018 and extracted their entire prescription history of specific systemic treatments from the Danish National Prescription Registry since its inception in 1995. The patients' treatment journeys are graphically displayed through Sankey diagrams and box plots generated to show temporal distributions. Descriptive patient characteristics were presented as frequencies with percentages for categorical variables and as means with SDs or medians with interquartile ranges (IQRs) for continuous variables.A total of 225 patients with HS were included. Patients had most frequently been treated with penicillin (n = 214; 95·1%), dicloxacillin (n = 194; 86·2%), tetracycline (n = 145; 64·4%) and rifampicin/clindamycin (n = 111; 49·3%), as well as the retinoids isotretinoin and acitretin, and dapsone. Prior to biologic therapy, patients received a mean of 4·0 (SD 1·3) different systemic therapies, across a mean of 16·9 (SD 11·3) different treatment series. The mean time from first systemic therapy until biologic therapy was initiated was 15·3 (SD 5·1) years [8·2 (SD 5·9) years when excluding penicillin and dicloxacillin].Patients with HS who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS. Delay in the initiation of biologic therapy may represent a missed opportunity to prevent disease progression. What is already known about this topic? The treatment journey leading to biologic therapy in patients with HS has not previously been investigated. What does this study add? Our data from 225 patients with HS illustrate that patients who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS.
Virtual exam for Parkinson’s disease enables frequent and reliable remote measurements of motor function
Authors: Maximilien Burq, Erin Rainaldi, King Chung Ho, Chen Chen, Bastiaan R. Bloem, Luc J. W. Evers, Rick C. Helmich, Lance Myers, William J. Marks, Ritu Kapur
Journal: npj Digital Medicine (2022)

Abstract Sensor-based remote monitoring could help better track Parkinson’s disease (PD) progression, and measure patients’ response to putative disease-modifying therapeutic interventions. To be useful, the remotely-collected measurements should be valid, reliable, and sensitive to change, and people with PD must engage with the technology. We developed a smartwatch-based active assessment that enables unsupervised measurement of motor signs of PD. Participants with early-stage PD ( N = 388, 64% men, average age 63) wore a smartwatch for a median of 390 days. Participants performed unsupervised motor tasks both in-clinic (once) and remotely (twice weekly for one year). Dropout rate was 5.4%. Median wear-time was 21.1 h/day, and 59% of per-protocol remote assessments were completed. Analytical validation was established for in-clinic measurements, which showed moderate-to-strong correlations with consensus MDS-UPDRS Part III ratings for rest tremor (⍴ = 0.70), bradykinesia (⍴ = −0.62), and gait (⍴ = −0.46). Test-retest reliability of remote measurements, aggregated monthly, was good-to-excellent (ICC = 0.75–0.96). Remote measurements were sensitive to the known effects of dopaminergic medication (on vs off Cohen’s d = 0.19–0.54). Of note, in-clinic assessments often did not reflect the patients’ typical status at home. This demonstrates the feasibility of smartwatch-based unsupervised active tests, and establishes the analytical validity of associated digital measurements. Weekly measurements provide a real-life distribution of disease severity, as it fluctuates longitudinally. Sensitivity to medication-induced change and improved reliability imply that these methods could help reduce sample sizes needed to demonstrate a response to therapeutic interventions or disease progression.
Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging
Authors: Chaoyue Wang, Aurea B. Martins-Bach, Fidel Alfaro-Almagro, Gwenaëlle Douaud, Johannes C. Klein, Alberto Llera, Cristiana Fiscone, Richard Bowtell, Lloyd T. Elliott, Stephen M. Smith, Benjamin C. Tendler, Karla L. Miller
Journal: Nature Neuroscience (2022)

Abstract A key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging magnetic resonance imaging technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We present an open resource of QSM-based imaging measures of multiple brain structures in 35,273 individuals from the UK Biobank prospective epidemiological study. We identify statistically significant associations of 251 phenotypes with magnetic susceptibility that include body iron, disease, diet and alcohol consumption. Genome-wide associations relate magnetic susceptibility to 76 replicating clusters of genetic variants with biological functions involving iron, calcium, myelin and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* signal decay time measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers worldwide, creating the potential to discover new, non-invasive markers of brain health.
68Ga-FAPI Versus 18F-FDG PET/CT in Recurrent Undifferentiated Pleomorphic Sarcoma of Colon Mesentery
Authors: Linqi Zhang, Zhidong Liu, Shuqin Jiang, Qiao He, Rusen Zhang
Journal: Clinical Nuclear Medicine (2022)

Abstract A 56-year-old woman presented with primary undifferentiated pleomorphic sarcoma of colon mesentery underwent complete surgical resection approximately 7 months ago. Abdominal contrast-enhanced CT showed a new mass in the descending colon, suggesting a high probability of tumor recurrence. Under a clinical trial, the patient underwent 68 Ga-FAPI and 18 F-FDG PET/CT to detect whether there are additional recurrent lesions. Compared with 18 F-FDG PET/CT, the recurrent undifferentiated pleomorphic sarcoma of colon mesentery, peritoneum, pelvic lymph node, and lung metastases showed higher uptake in 68 Ga-FAPI PET/CT. This case showed that 68 Ga-FAPI might be a promising radiopharmaceutical in the evaluation of undifferentiated pleomorphic sarcoma.
Evolutionary Conservation Genomics Reveals Recent Speciation and Local Adaptation in Threatened Takins
Authors: Lin Yang, Fuwen Wei, Xiangjiang Zhan, Huizhong Fan, Pengpeng Zhao, Guangping Huang, Jiang Chang, Yinghu Lei, Yibo Hu
Journal: Molecular Biology and Evolution (2022)

Abstract Incorrect species delimitation will lead to inappropriate conservation decisions, especially for threatened species. The takin (Budorcas taxicolor) is a large artiodactyl endemic to the Himalayan–Hengduan–Qinling Mountains and is well known for its threatened status and peculiar appearance. However, the speciation, intraspecies taxonomy, evolutionary history, and adaptive evolution of this species still remain unclear, which greatly hampers its scientific conservation. Here, we de novo assembled a high-quality chromosome-level genome of takin and resequenced the genomes of 75 wild takins. Phylogenomics revealed that takin was positioned at the root of Caprinae. Population genomics based on the autosome, X chromosome, and Y chromosome SNPs and mitochondrial genomes consistently revealed the existence of two phylogenetic species and recent speciation in takins: the Himalayan takin (B. taxicolor) and the Chinese takin (B. tibetana), with the support of morphological evidence. Two genetically divergent subspecies were identified in both takin species, rejecting three previously proposed taxonomical viewpoints. Furthermore, their distribution boundaries were determined, suggesting that large rivers play important roles in shaping the genetic partition. Compared with the other subspecies, the Qinling subspecies presented the lowest genomic diversity, higher linkage disequilibrium, inbreeding, and genetic load, thus is in urgent need of genetic management and protection. Moreover, coat color gene (PMEL) variation may be responsible for the adaptive coat color difference between the two species following Gloger’s rule. Our findings provide novel insights into the recent speciation, local adaptation, scientific conservation of takins, and biogeography of the Himalaya–Hengduan biodiversity hotspot.
Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With <i>ALK</i>-Positive Advanced Non–Small-Cell Lung Cancer From the Phase III CROWN Study
Authors: Benjamin J. Solomon, Todd M. Bauer, Sai-Hong Ignatius Ou, Geoffrey Liu, Hidetoshi Hayashi, Alessandra Bearz, Konstantin Penkov, Yi-Long Wu, Oscar Arrieta, Jacek Jassem, Anna M. Calella, Gerson Peltz, Anna Polli, Holger Thurm, Tony Mok
Journal: Journal of Clinical Oncology (2022)

PURPOSE Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK-positive non–small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN. METHODS Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted. RESULTS PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS. CONCLUSION First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK-positive non–small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.
Inflammatory bowel disease biomarkers
Authors: Dandan Liu, Varma Saikam, Katie A. Skrada, Didier Merlin, Suri S. Iyer
Journal: Medicinal Research Reviews (2022)

Abstract Inflammatory bowel disease (IBD) is characterized as chronic inflammation in the gastrointestinal tract, which includes two main subtypes, Crohn&amp;#39;s disease and ulcerative colitis. Endoscopy combined with biopsy is the most effective way to establish IBD diagnosis and disease management. Imaging techniques have also been developed to monitor IBD. Although effective, the methods are expensive and invasive, which leads to pain and discomfort. Alternative noninvasive biomarkers are being explored as tools for IBD prognosis and disease management. This review focuses on novel biomarkers that have emerged in recent years. These serological biomarkers and microRNAs could potentially be used for disease management in IBD, thereby decreasing patient discomfort and morbidity.
Innate immune mediator, Interleukin-1 receptor accessory protein (IL1RAP), is expressed and pro-tumorigenic in pancreatic cancer
Authors: Yang Zhang, Xiaoyi Chen, Huamin Wang, Shanisha Gordon-Mitchell, Srabani Sahu, Tushar D. Bhagat, Gaurav Choudhary, Srinivas Aluri, Kith Pradhan, Plabani Sahu, Milagros Carbajal, Hui Zhang, Beamon Agarwal, Aditi Shastri, Robert Martell, Daniel Starczynowski, Ulrich Steidl, Anirban Maitra, Amit Verma
Journal: Journal of Hematology & Oncology (2022)

Abstract Advanced pancreatic ductal adenocarcinoma (PDAC) is usually an incurable malignancy that needs newer therapeutic targets. Interleukin-1 receptor accessory protein (IL1RAP) is an innate immune mediator that regulates activation of pro-inflammatory and mitogenic signaling pathways. Immunohistochemistry on tissue microarrays demonstrated expression of IL1RAP in majority of human PDAC specimens and in murine pancreatic tumors from K-Ras G122D /p53 R172H /PDXCre (KPC) mice. Single cell RNA-Seq analysis of human primary pre-neoplastic lesions and adenocarcinoma specimens indicated that overexpression occurs during carcinogenesis. IL1RAP overexpression was associated with worse overall survival. IL1RAP knockdown significantly reduced cell viability, invasiveness, and clonogenic growth in pancreatic cancer cell lines. Inhibition of the downstream interleukin-1 receptor-associated kinase 4 (IRAK4) using two pharmacologic inhibitors, CA-4948 and PF06650833, resulted in reduced growth in pancreatic cancer cell lines and in xenograft models.
Efficacy of anti–SARS-CoV-2 monoclonal antibody prophylaxis and vaccination on the Omicron variant of COVID-19 in kidney transplant recipients
Authors: Dominique Bertrand, Charlotte Laurent, Veronique Lemée, Ludivine Lebourg, Mélanie Hanoy, Frank Le Roy, Dorian Nezam, Diana Pruteanu, Steven Grange, Tristan de Nattes, Mathilde Lemoine, Sophie Candon, Dominique Guerrot
Journal: Kidney International (2022)
Gut microbiota predicts body fat change following a low-energy diet: a PREVIEW intervention study
Authors: Ching Jian, Marta Paulino Silvestre, Danielle Middleton, Katri Korpela, Elli Jalo, David Broderick, Willem Meindert de Vos, Mikael Fogelholm, Mike William Taylor, Anne Raben, Sally Poppitt, Anne Salonen
Journal: Genome Medicine (2022)

Abstract Background Low-energy diets (LEDs) comprise commercially formulated food products that provide between 800 and 1200 kcal/day (3.3–5 MJ/day) to aid body weight loss. Recent small-scale studies suggest that LEDs are associated with marked changes in the gut microbiota that may modify the effect of the LED on host metabolism and weight loss. We investigated how the gut microbiota changed during 8 weeks of total meal replacement LED and determined their associations with host response in a sub-analysis of 211 overweight adults with pre-diabetes participating in the large multicentre PREVIEW (PREVention of diabetes through lifestyle intervention and population studies In Europe and around the World) clinical trial. Methods Microbial community composition was analysed by Illumina sequencing of the hypervariable V3-V4 regions of the 16S ribosomal RNA (rRNA) gene. Butyrate production capacity was estimated by qPCR targeting the butyryl-CoA:acetate CoA-transferase gene. Bioinformatics and statistical analyses, such as comparison of alpha and beta diversity measures, correlative and differential abundances analysis, were undertaken on the 16S rRNA gene sequences of 211 paired (pre- and post-LED) samples as well as their integration with the clinical, biomedical and dietary datasets for predictive modelling. Results The overall composition of the gut microbiota changed markedly and consistently from pre- to post-LED ( P = 0.001), along with increased richness and diversity (both P &lt; 0.001). Following the intervention, the relative abundance of several genera previously associated with metabolic improvements (e.g., Akkermansia and Christensenellaceae R-7 group) was significantly increased ( P &lt; 0.001), while flagellated Pseudobutyrivibrio , acetogenic Blautia and Bifidobacterium spp. were decreased (all P &lt; 0.001). Butyrate production capacity was reduced ( P &lt; 0.001). The changes in microbiota composition and predicted functions were significantly associated with body weight loss ( P &lt; 0.05). Baseline gut microbiota features were able to explain ~25% of variation in total body fat change (post–pre-LED). Conclusions The gut microbiota and individual taxa were significantly influenced by the LED intervention and correlated with changes in total body fat and body weight in individuals with overweight and pre-diabetes. Despite inter-individual variation, the baseline gut microbiota was a strong predictor of total body fat change during the energy restriction period. Trial registration The PREVIEW trial was prospectively registered at ClinicalTrials.gov ( NCT01777893 ) on January 29, 2013.
Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma
Authors: Pavlina Chuntova, Akane Yamamichi, Tiffany Chen, Rohini Narayanaswamy, Sebastien Ronseaux, Christine Hudson, Adriana E Tron, Marc L Hyer, Megan Montoya, Abigail L Mende, Takahide Nejo, Kira M Downey, David Diebold, Min Lu, Brandon Nicolay, Hideho Okada
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the ‘cold’ tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade. Methods An IDH1 R132H glioma model was created in syngeneic HLA-A2/HLA-DR1 -transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1 R132H mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1 R132H peptide vaccination or anti-PD-1 immune checkpoint blockade. Results The HLA-A2/HLA-DR1 -syngeneic IDH1 R132H cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1 R132H glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1 R132H gliomas. AG-881 monotherapy suppressed the progression of IDH1 R132H gliomas in a CD4 + and CD8 + cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4 + tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1 R132H peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1 R132H and DR1-IDH1 R132H peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone. Conclusion The development of effective IDH1 R132H -targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our HLA-A2/HLA-DR1 -syngeneic IDH1 R132H glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.
Salt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation
Authors: Antonio Sorrentino, Ayse Nur Menevse, Tillmann Michels, Valentina Volpin, Franziska Christine Durst, Julian Sax, Maria Xydia, Abir Hussein, Slava Stamova, Steffen Spoerl, Nicole Heuschneider, Jasmin Muehlbauer, Katharina Marlene Jeltsch, Anchana Rathinasamy, Melanie Werner-Klein, Marco Breinig, Damian Mikietyn, Christian Kohler, Isabel Poschke, Sabrina Purr, Olivia Reidell, Catarina Martins Freire, Rienk Offringa, Claudia Gebhard, Rainer Spang, Michael Rehli, Michael Boutros, Christian Schmidl, Nisit Khandelwal, Philipp Beckhove
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Cancer immunotherapeutic strategies showed unprecedented results in the clinic. However, many patients do not respond to immuno-oncological treatments due to the occurrence of a plethora of immunological obstacles, including tumor intrinsic mechanisms of resistance to cytotoxic T-cell (TC) attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies. Methods To identify novel genes that protect tumor cells from effective TC-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with tumor-infiltrating lymphocytes and antigen-specific TCs. Results The screening revealed 108 potential genes that protected tumor cells from TC attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibitions of SIK3 in tumor cells dramatically increased TC-mediated cytotoxicity in several in vitro coculture models, using different sources of tumor and TCs. Consistently, adoptive TC transfer of TILs led to tumor growth inhibition of SIK3-depleted cancer cells in vivo. Mechanistic analysis revealed that SIK3 rendered tumor cells susceptible to tumor necrosis factor (TNF) secreted by tumor-activated TCs. SIK3 promoted nuclear factor kappa B (NF- κB) nuclear translocation and inhibited caspase-8 and caspase-9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of prosurvival genes under the TNF–NF- κB axis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase and NF-kappa-B inhibitor alpha on the one side, and to inhibition of histone deacetylase 4 on the other side, thus sustaining NF-κB activation and nuclear stabilization. A SIK3-dependent gene signature of TNF-mediated NF-κB activation was found in a majority of pancreatic cancers where it correlated with increased cytotoxic TC activity and poor prognosis. Conclusion Our data reveal an abundant molecular mechanism that protects tumor cells from cytotoxic TC attack and demonstrate that pharmacological inhibition of this pathway is feasible.